In situ extension as an approach for identifying novel α-amylase inhibitors.
Open accessAbstract
A new approach for the discovery and subsequent structural elucidation of oligosaccharide-based inhibitors of alpha-amylases based upon autoglucosylation of known alpha-glucosidase inhibitors is presented. This concept, highly analogous to what is hypothesized to occur with acarbose, is demonstrated with the known alpha-glucosidase inhibitor, d-gluconohydroximino-1,5-lactam. This was transformed from an inhibitor of human pancreatic alpha-amylase with a K(i) value of 18 mm to a trisaccharide analogue with a K(i) value of 25 mum. The three-dimensional structure of this complex was determined by x-ray crystallography and represents the first such structure determined with this class of inhibitors in any alpha-glycosidase. This approach to the discovery and structural analysis of amylase inhibitors should be generally applicable to other endoglucosidases and readily adaptable to a high throughput format.
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The initial automatic preparation of structures performed by PDBbind did not provide an optimized hydrogen bond network and appropriate assignment of protonation/tautomeric states of the α-amylase and MeG2-GHIL complex.
“For example, the initial automatic preparation of the structures performed by PDBbind did not provide an optimized hydrogen bond network and appropriate assignment of protonation/tautomeric states of the α-amylase and MeG2-GHIL complex [Figure 1, PDB code 1U33; Numao et al., 2004].”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Numao et al., 2004
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- Authors
- Numao, S., Damager, I., Li, C., Wrodnigg, T. M., Begum, A., Overall, C. M., Brayer, G. D., & Withers, S. G.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Withers, Stephen G.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-11
- Volume
- 279
- Issue
- 46
- Pages
- 48282-48291
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2041943011
- Cited by
- 24
- References
- 38
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 2 · 2019: 1 · 2018: 2 · 2016: 1 · 2014: 4 · 2012: 2
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Carlsbergfondet
- Canadian Institutes of Health Research
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- alpha-amylase inhibitors, alpha-glucosidase inhibitors, acarbose, pancreatic alpha-amylase, enzyme-inhibitor complex structure
- MeSH terms
- alpha-Amylases, Animals, Binding Sites, Carbohydrate Sequence, Enzyme Inhibitors, Humans, Models, Molecular, Pancreas, Protein Binding, Trisaccharides, Drug Design, Molecular Structure, Protein Structure, Tertiary, Crystallography, X-Ray, Acarbose
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